Arsenic is a naturally occuring metal that has contaminated the ground water of Western, Midwestern and Northeastern areas of the United States, largely as a result of minerals dissolving from weathered rocks and soils. Arsenic has been recognized as a human toxicant since ancient times and has been linked to the development of skin, kidney, lung, bladder, and liver cancers. Additionally, a variety of non-cancerous conditions such as hypertension, cardiovascular disease and diabetes mellitus have been associated with chronic ingestion of low levels of arsenic. The majority of arsenic-associated diabetes mellitus studies have focused on epidemiological studies of exposed populations, yet little is known about the biochemical mechanisms that maybe aberrantly affected by chronic exposure to low levels of arsenic. Our group has been able to show that exposure to arsenic in drinking water as low as 10 ppb (0.13 5M) could produce hyperinsulemia in C57Bl/6 mice. Additional studies performed by our group in mature adipocytes show an increase in secretion of cytokines, such as IL-6 and curiosly NT-3, in response to low level arsenic exposure (50 ppb). To our knowledge this is the first evidence that the neurotrophin, NT-3, can be secreted by 3T3-L1 adipocytes in response to arsenic exposure. For this reason, the objective of this application is to define the and characterize mechanism(s) by which NT-3 is being secreted by arsenic exposure and the downstream consequences it produces. Hence, our central hypothesis is that chronic exposure to low levels of arsenic results in insulin-resistance and hyperinsulimia in insulin-responsive cells due to arsenic-induced cytokine secretion. PUBLIC HEALTH RELEVANCE: Diabetes is a group of diseases that are characterized by high levels of blood glucose resulting from defects in insulin production or from insulin-resistance. The number of diagnosed cases of the disease have more than doubled over the past ten years and amongst these, Type 2 diabetes accounts for 90-95%. Risk factors associcated with Type 2 diabetes include aging, obesity, family history as well as exposure to environmental factors such as arsenic. Knowledge of how arsenic interrupts normal blood-glucose regulation will help to elucidate the etiological factors behind the progression of Type 2 diabetes mellitus.